A randomized phase I/II study to examine the contribution of carboplatin to cabazitaxel for the treatment of men with metastatic castration-resistant prostate cancer (mCRPC) with and without anaplastic features.

Abstract

148 Background: We recently described “anaplastic” prostate carcinomas (PC), a clinically distinct variant of lethal castration-resistant prostate cancer (CRPC) that share clinical features with small cell carcinomas despite heterogeneous morphology. To test the hypothesis that anaplastic PC are uniquely sensitive to platinum-based chemotherapy, we designed a randomized study of cabazitaxel with or without carboplatin in men with metastatic CRPC (mCRPC) stratified for the presence of at least 1 of 7 previously published anaplastic criteria (Aparicio, Clin Cancer Res 2013;19). Here we report results of the phase I study. Methods: Patients (pts) received intravenous cabazitaxel with carboplatin every 21 days with growth factor support and were imaged every two cycles. A 3+3 sequential dose-escalation design was employed to assess the frequency of dose-limiting toxicity after cycle one and establish a maximal tolerated dose (MTD). Three cohorts were tested: (i) cabazitaxel 20mg/m2 – carboplatin AUC 3, (ii) cabazitaxel 25 mg/m2 – carboplatin AUC 3, and (iii) cabazitaxel 25 mg/m2 - carboplatin AUC 4. Up to 10 cycles were administered in the absence of progression or toxicity. Results: Nine men with mCRPC (five anaplastic) previously treated with docetaxel, received a median of six cycles (2 to 10). All had bone involvement and 6 of 9 had RECIST measurable disease. An MTD was not identified. All pts reported 1 or more adverse event (AE) possibly treatment related (120 Grade 1; 53 Grade 2; 13 Grade 3), most commonly fatigue, anemia, nausea, and diarrhea. Grade 3 AE included anemia (n=2), fatigue (n=1), thrombocytopenia (n=1), hypomagnesemia (n=1), diarrhea (n=1), hypokalemia (n=1), and anorexia (n=1). Prostate-specific antigen declines of more than 70% occurred in 6 of 9 (67%) pts. Two of 6 pts had a partial response, three had stable disease, and one progressed. For pts with elevated bone markers at baseline, 2 of 3 had more than 50% declines in BAP and 4 of 7 had more than 30% declines in urinary N-telopeptide levels. Conclusions: The combination of cabazitaxel and carboplatin is safe and has significant clinical activity. The randomized phase II portion combines cabazitaxel 25 mg/m2 and carboplatin AUC4. Results will be updated at the time of the meeting. Clinical trial information: NCT01505868.